title: Retargeting NK-92 for anti-melanoma activity by a TCR-like single-domain antibody.
abstract: The efficacy of immunotherapy based on natural killer (NK) cells is hampered by intrinsic non-specific cytotoxicity and insufficient activation of NK cells. Here, we confer the T-cell receptor-like (TCR-like) specificity on NK cells, taking advantage of both the innate and adaptive immune arms of the immune response to generate enhanced anti-melanoma activity. The TCR-like antibody (Ab) GPA7 was selected against melanoma-associated gp100/human leukocyte antigen (HLA)-A2 complex and then fused to intracellular domain of CD3-ζ chain. This fusion construct was incorporated into NK-92MI cell line and expressed as a chimeric antigen receptor on the surface of the cell. The anti-tumour activity of the transgenic NK-92MI-GPA7-ζ cell line was assessed against melanoma in vitro and in vivo. The engineered NK-92MI-GPA7-ζ cells could recognize melanoma cells in the context of HLA-A2 and showed enhanced killing of both melanoma cell lines and primary melanoma. Furthermore, adoptively transferred NK-92MI-GPA7-ζ cells significantly suppressed the growth of human melanoma in a xenograft model in mice. Collectively, these results demonstrate that the TCR-like Ab, GPA7, could redirect NK cells to target the intracellular antigen gp100 and enhance anti-melanoma activity, providing a promising immunotherapeutic strategy to prevent and treat melanoma.
authors.affiliation: 1] The Centre for Molecular Immunology and China-Japan Joint Laboratory of Molecular Immunology and Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China [2] University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Rongzhi
authors.initials: R
authors.lastname: Liu
authors.forename: Xuekai
authors.initials: X
authors.lastname: Zhu
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.forename: Huamin
authors.initials: H
authors.lastname: Han
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Ganlin
authors.initials: G
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Changzhen
authors.initials: C
authors.lastname: Liu
authors.forename: Shenghua
authors.initials: S
authors.lastname: Li
authors.forename: Meiyi
authors.initials: M
authors.lastname: Sun
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055503:Protein Multimerization; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D061905:Single-Domain Antibodies / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011948:Receptors, Antigen, T-Cell; D061905:Single-Domain Antibodies